1. Field of the Invention
The present invention relates generally to chemical or drug substances in the blood as they relate to physical dependence. The present invention relates to a method and dosages for controlling the elimination of a chemical or drug substance in blood in order to eliminate physical dependence to these and related chemicals or drug substances.
2. Description of the Prior Art
There are numerous legal and illegal chemical or drug substances currently available in the marketplace. Certain types of chemical or drug substances that are taken repeatedly cause the body to develop a physical dependence for the chemical or drug substance. This physical dependence for some of chemicals and drug substances is called an addiction. Discontinuation of the substance by an individual who has developed a physical dependence for the chemical or drug substance typically causes untoward withdrawal symptoms in the individual.
Examples of chemical or drug substances that can lead to physical dependence include alcohol, opioids (morphine, codeine, thebaine, hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine, diacetylmorphine or heroin, nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine, fentanyl, pethidine, methadone, tramadol, propxyphene), amphetamines and derivatives such as MDMA (3,4-Methylenedioxy-N-methamphetamine) and methamphetamine, barbiturates (allobarbital, amobarbital, aprobarbital, alphenal, barbital, brallobarbital, Phenobarbital), benzodiazepines both hypnotic (estazolam, flurazepam, midazolam, triazolam, temazepam, nimetazepam, brotizolam, flunitrazepam, loprazolam, lormetazepam, and nitrazepam), and anxiolytic (alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam, oxazepam, prazepam, and bromazepam), gamma-hydroxybutyric acid, methaqualone, cocaine, anticonvulsants (acetazolamide, carbamazepine, clobazam, clonazepam, diazepam, divalproex sodium, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, mephenytoin, metharbital, methsuximide, methazolamide, oxycarbazepine, Phenobarbital, phenytoin, phensuximide, pregabalin, primidone, valproic acid, stiripentol, tiagabine, topiramate, trimethadione, vigabatrin, and zonisamide); mood stabilizers (lithium salts, valproic acid, divalproex sodium, sodium valproate, lamotrigine, carbamazepine, gabapentin, oxcarbazepine, and topiramate), antipsychotics (first generation—butyrophenones such as haloperidol, phenothiazines such as chlorpromazine, fluphenazine, perphenazine, thioridazine, trifluoperazine, mesoridazine, promethazine, triflupromazine, and levomepromazine, thioxanthenes such as chlorprothixine, thiothixene, flupenthixol, and zuclopenthixol); second generation—clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and derivatives; third generation—aripiprazole; and others such as tetrabenazine and cannabinoids; antidepressants (serotonin-norepinephrine reuptake inhibitors—SSRIs—include fluoxetine, paroxetine, escitalopram, citalopram, and sertraline; serotonin-norepinephrine reuptake inhibitors—SNRIs—include venlafaxine and duloxetine; noradrenergic and specific serotonergic antidepressnats—NASSAs—such as mirtazapine; norepinephrine reuptake inhibitors—NRIs—such as reboxetine; norepinephrine-dopamine reuptake inhibitors such as bupropion; tricyclic antidepressants—TCAs—such as amitriptyline, imipramine, desipramine, trazodone, and nortriptyline; monoamine oxidase inhibitors—MAOIs—such as phenelzine, moclobenmide; buspirone); methylxanthines such as caffeine, theophylline, and theobromine; nicotine; methylphenidate; and other drugs that act on the nervous systems either central or peripheral, or both. Other chemical or drug substances that do not primarily act on the central nervous system can also cause withdrawal, including antihypertensives in particular beta blockers, and glucosteroids.
For many of these chemicals and drug substances, the central nervous system effects are more noticeable. They act by preventing the uptake of the normal neurotransmitters such as dopamine, serotonin and norepinephrine, and establish new pathways for neurotransmission and cellular function. The peripheral nervous system, however, is also affected, involving disparate parts of the body such as the heart or gastrointestinal system.
Following repeated exposure on a prolonged basis, the body systems develop physical dependence by adapting to the uptake of the administered chemical or drug substances as they seek new conditions of homeostasis. When abrupt change to the new homeostasis occurs, unpleasant and sometimes life threatening withdrawal symptoms accompany rapid cessation in dosing. Withdrawal symptoms may include dizziness, light-headedness, vertigo or feeling faint, shock-like sensations or paresthesia, anxiety, diarrhea, fatigue, instability, headache, insomnia, irritability, nausea or vomiting, palpitations, tremor, and visual disturbances. Craving in the case of addictive chemical or drug substances can occur either earlier or later following cessation of intake. More serious withdrawal effects may include convulsions, hallucinations, catatonia, coma, suicidal tendencies, hyperthermia, violence, and psychosis. Fatality may occur under certain situations such as mediated by cardiac arrest.
To be more precise, neurotransmitters are various chemical substances that include monoamines (dopamine, epinephrine, norepinephrine, serotonin, and melatonin), amino acids (glutamic acid, gamma aminobutyric acid, aspartic acid and glycine), peptides (vasopressin, somatostatin, etc.), and others such as adenosine, histamine, etc., that through binding to receptors mediate neurotransmission. When chemical or drug substances that cause physical dependence competitively bind to specific receptors, accumulation of specific neurotransmitters can occur. For instance, dopamine levels can increase in the nucleus accumbens, and cause the euphoria associated with opiate use. The usual doses of chemical or drug substances may saturate the receptors. After extended periods of repeated dosing, a sudden withdrawal of the chemical or drug substance can deplete the neurotransmitters that had been released, and precipitate the withdrawal symptoms.
Traditional methods for treatment of dependence involve either very rapid tapering of the drug substance, e.g. nicotine transdermal patches (Habitrol) for smoking cessation or through replacement therapy, e.g. methadone and buprenorphine (Suboxone®/Subutex®), at sustained relatively high doses.
Conventional therapies for opioid addiction treatment are replacement therapies using other opioid agonists. Methadone and buprenorphine replacement therapies are typically aimed at maintenance therapy, not at total cessation. As an example, patients in maintenance treatment with methadone should be titrated to a dose at which opioid symptoms are prevented for 24 hours, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are blocked or attenuated, and the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.
In the case of buprenorphine, the goal is to achieve an optimal maintenance dose. The steps include adjusting the dose until the maintenance dose is achieved. The recommended target dose of Suboxone® is 16 mg/day. Clinical studies have shown that 16 mg of Subutex® or Suboxone® is a clinically effective dose compared with placebo and indicate that doses as low as 12 mg/day may be effective in some patients. The dosage of Suboxone® should be progressively adjusted in increments/decrements of 2 mg or 4 mg to a level that holds the patient in treatment and suppresses opioid withdrawal effects. This is likely to be in the range of 4 mg to 24 mg per day depending on the individual.
Although it has been recognized by many that one way to prevent withdrawal symptoms is through tapering the patient off the medication that led to the physical dependence in the first place, the practice is variable and usually deficient. Examples of inadequacies in the current state of practice of tapering will now be described.
Treatment for alcohol withdrawal is not based on the tapering concept at all, but is designed to treat the side effects which can be fatal. For instance, benzodiazapines are the first line treatment for delirium tremens, with addition of phemobarbital or propofol should the former not be effective.
A survey on the actual practice of tapering shows that the instructions are either absent or vague or that tapering is done in such large decrements that they cause sudden blood level changes.
For serotonin and norepinephrine reuptake inhibitors such as venaflexane, a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then the recommendation is to resume the previously prescribed dose. In fact, the instructions state that symptoms associated with discontinuation of Effexor XR®, other SNRIs, and SSRIs, have been reported. Patients should be monitored for these symptoms when discontinuing treatment. In clinical trials with Effexor XR®, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals, however, individualization of tapering may be necessary.
For paroxetine, the instructions for the discontinuation of treatment with Paxil® state that recent clinical trials supporting the various approved indications for Paxil® employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped.
Furthermore, there is a trial and error mode in methods to be used to avoid withdrawal. For paroxetine, the instructions for the discontinuation of treatment with PAXIL C® state that symptoms associated with discontinuation of immediate-release paroxetine hydrochloride or PAXIL CR® have been reported and further instruct to see the precautions. The instructions go on to state that patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which PAXIL CR® is being prescribed. Like serotonin and norepinephrine reuptake inhibitors, gradual reduction in the dose of paroxetine rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Likewise for sertraline hydrochloride, the instructions state a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
For amphetamines, there is no current stated practice of dealing with physical dependence.
For benzodiazepines such as Chlorazepate, the instructions state that after extended therapy, abrupt discontinuation of Clorazepate should generally be avoided and a gradual dosage tapering schedule followed.
For methadone, the official prescribing information states that there is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. The information further states that patients should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.
For buprenorphine, the official prescribing information states the following regarding reducing dosage and stopping treatment: The decision to discontinue therapy with Suboxone® or Subutex® after a period of maintenance or brief stabilization should be made as part of a comprehensive treatment plan. Both gradual and abrupt discontinuations have been used, but no controlled trials have been undertaken to determine the best method of dose taper at the end of treatment.
For fentanyl, the official prescribing information states the following for the discontinuation of DURAGESIC®. For patients requiring discontinuation of opioids, a gradual downward titration is recommended since it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.
For smoking cessation using nicotine, very large reduction steps are recommended. The resultant clinical success rates are low, at 6-12% over placebo.
Therefore, what is needed is a tapering system that provides for the complete cessation of any chemical or drug substance without the occurrence of withdrawal symptoms.